Studies have been performed to determine the mechanism of cytotoxicity by mouse natural cytotoxic (NC) cells and to contrast this information with the mechanism for cytotoxicity by natural killer (NK) cells. The NC-susceptible target cell, WEHI-164, has been found to be highly susceptible to both mouse and human recombinant tumor necrosis factor (TNF) and antibodies to mouse TNF strongly inhibited NC activity. In contrast, the NK-susceptible target cell YAC-1 was resistant to lysis by TNF and anti-TNF did not affect NK activity. Studies have continued on the regulation of mouse NK activitiy. The development of NK activity after birth was found to be appreciably accelerated by repeated inoculations of infant mice with interluekin 2 (IL-2). Similarly, repeated inoculations of low doses of IL-2 were able to induce more rapid reconstitution of NK activity by donor bone marrow cells in lethally irradiated mice. These results point to an important role of IL-2 in the in vivo differentiation or expansion of mouse NK cells. Mouse model systems for induction of hyporesponsiveness to augmentation of KN activity, after multiple inoculations of natural or recominant interferon, have been developed. This hyporesponsiveness was found to be generalized, not only in the blood or spleen but also inthe liver and lungs. Subsequent inoculation with other biological response modifiers, such as IL-2, poly ICLC or MVE-2, resulted in substantial augmentation of KN activity, pointing toward a combination treatment approach to overcoming the NK hyporesponsiveness. Studies have been performed on the regulation of mouse NK activity by 17Beta-estradiol. As previously described, prolonged treatment resulted in depressed NK activity which was associated with decreased number of large granular lymphocytes (LGL). In contract, shorter periods of treatment with this estrogenic hormone resulted in augmented NK activity and increased numbers of LGL. These results indicate that hormonal regulation of NK activity is more complex than previously realized and that estrogens can have both positive and negative regulatory effects.